Nocebo and lessebo effects.

The power of placebos is commonly associated with the placebo effect. In contrast, detrimental effects related to the use of a placebo are little studied and less well recognized. This chapter covers the nocebo and lessebo effects defined, respectively, as expectation of harm in the form of adverse events in a placebo arm and reduction of therapeutic benefit due to the uncertainty of being allocated to placebo. The lessebo effect is a more recent concept and has been described only in depression, schizophrenia and Parkinson's disease. The nocebo response was evaluated in many neurological diseases, including epilepsy, multiple sclerosis, Parkinson's disease, Alzheimer's disease, restless leg syndrome, among others. Meta-analyses of randomized controlled trials in these conditions reveal a significant variability of the magnitude of the nocebo response and that factors related to study design, study participants or neurological disease can be associated with a nocebo response, although with the opposing findings across conditions. The knowledge about neurobiological mechanisms of the nocebo effect is poor for neurological diseases, and most of the information has been generated in pain. Functional neuroimaging suggests the existence of a distinct network for the anticipation and the experience of a hyperalgesia nocebo response. Different types of neurotransmitters have been involved, including cholecystokinin, dopamine and opioids. Recognizing the potential impact of nocebo and lessebo effects, mitigating strategies are in development with application to clinical research and clinical practice, such as a contextualized informed consent process, alternative study designs and enhancement of patient-physician communication.